WO2000066552A1 - Procede de production d'un derive de benzoylguanidine - Google Patents

Procede de production d'un derive de benzoylguanidine Download PDF

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Publication number
WO2000066552A1
WO2000066552A1 PCT/EP2000/003455 EP0003455W WO0066552A1 WO 2000066552 A1 WO2000066552 A1 WO 2000066552A1 EP 0003455 W EP0003455 W EP 0003455W WO 0066552 A1 WO0066552 A1 WO 0066552A1
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Prior art keywords
methyl
group
methylsulfonyl
reaction
formula
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PCT/EP2000/003455
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German (de)
English (en)
Inventor
Manfred Baumgarth
Rolf Gericke
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Merck Patent Gmbh
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Publication date
Application filed by Merck Patent Gmbh filed Critical Merck Patent Gmbh
Priority to AU41190/00A priority Critical patent/AU4119000A/en
Publication of WO2000066552A1 publication Critical patent/WO2000066552A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/14—Sulfones; Sulfoxides having sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings

Definitions

  • the present invention relates to a process for the preparation of the benzoylguanidine derivative N- (diaminomethylene) -2-methyl-5- (methylsulfonyl) -4- (pyrrol-1-yl) benzamide, methanesulfonate (eniporide).
  • This substance is an NHE-1 selective Na + / H + - antiporter inhibitor.
  • Heterocyclyl-benzoylguanidines are known and are described, for example, in EP 0 699 666 A1. These substances are inhibitors of the cellular Na + / H + antiporter, ie active substances which inhibit the Na + / H + exchange mechanism of the cells (Düsing et al., Med. Klin. 87, 367-384, 1992) and thus represent good antiarrhythmics.
  • these compounds can also be used as therapeutic agents in diseases caused by cell proliferation, such as arteriosclerosis, late diabetic complications, tumor diseases, fibrotic diseases, in particular of the lungs, liver and kidneys, and organ hypertrophies and hyperplasias.
  • the compounds are suitable for diagnostic use for the detection of diseases which are accompanied by an increased activity of the Na + / H + antiporter, for example in erythrocytes, thromobocytes or leukocytes.
  • the compounds can therefore be used as active pharmaceutical ingredients in human and veterinary medicine. They can also be used as intermediate Find products for the production of other active pharmaceutical ingredients.
  • Methanesulfonate (eniporide), crystallized out. This substance not only has a very good cardioprotective effect when given before an experimentally induced ischemia, but also shows healing effects when the symptoms of an acute myocardial infarction have already started. In addition to use in acute myocardial infarction, Eniporide is intended for perioperative cardioprotection, i.e. to protect the heart from and during major operations.
  • the known syntheses comprise a large number of individual steps with unsatisfactory yields and also with difficult reaction conditions, e.g. Low temperature reactions.
  • the invention relates to a process for the preparation of the benzoylguanidine derivative N- (diaminomethylene) -2-methyl-5- (methylsulfonyl) -4- (pyrrol-l-yl) benzamide, methanesulfonate (eniporide) of the formula I,
  • Me is a methyl group, which is characterized in that in the first step by reacting the starting compound of the formula II
  • Me is a methyl group and R is fluorine or chlorine
  • the methanesulfonyl group is introduced in a one-step reaction, the entry of the new substituent being directed into the para position to the methyl group, then in the second step the bromine is exchanged for the carboxyl group by a palladium-catalyzed carbonylation reaction in the autoclave at elevated pressure and temperature,
  • the pyrrole group is introduced by a nucleophilic halogen-pyrrole exchange and the compound of the formula III is obtained,
  • the Z-protecting group is cleaved off by catalytic hydrogenation, wherein after the catalyst has been suctioned off, the sensitive base released as an intermediate is not worked up, but rather directly from the hydrogenation solution Salt is precipitated.
  • Methyl iodide achieved at -90 ° to - 80 ° C. Then the methylsulfonyl group is introduced there in three stages (sulfochlorination, reduction and methylation).
  • the introduction of the pyrrole group is conventionally accomplished by substitution with benzylamine, catalytic hydrogenation, esterification and reaction with 2,5-dimethoxytetrahydrofuran in 4 steps to give 2-methyl-5-methylsulfonyl-4-pyrrolyl-benzoic acid methyl ester.
  • the last step in the synthesis is to replace the methyl benzoate obtained with excess guanidine in methanol
  • the process now present in this invention significantly reduces the number of reaction steps, the overall yield is increased considerably and one has a preparatively simpler, and therefore more economical process.
  • Another advantage is that in the process according to the invention the sensitive base does not have to be isolated and purified, but can be precipitated directly from the reaction solution as methanesulfonate.
  • the methanesulfonyl group is now like a Friedel-Crafts
  • the methanesulfonic anhydride is intermediate
  • Heating methanesulfonic acid is formed with thionyl chloride.
  • the Friedel-Crafts catalyst - in addition to the catalysts commonly used for this - is mainly trifluoromethanesulfonic acid. With this compound as a catalyst, the best yields are obtained in this reaction.
  • the addition of the starting compound II and the catalyst to the methanesulfonic anhydride is advantageously carried out at room temperature, if appropriate with cooling, and the mixture is then heated to complete the reaction.
  • the advantage of this process step is that the methanesulfonyl group can be introduced into the molecule in one step - compared to three steps in the conventional process.
  • the carboxyl group is converted by a palladium-catalyzed carbonylation reaction (cf. T. W. Ku et al., Tetrahedron Lett. 1997, 38, 3131-3134;
  • the pyrrole group is introduced.
  • the introduction of the pyrrole group is accomplished by substitution with benzylamine, catalytic hydrogenation, esterification and reaction with 2,5-dimethoxytetrahydrofuran in 4 steps to give methyl 2-methyl-5-methylsulfonyl-4-pyrrolylbenzoate, the correspondingly free result in the method according to the invention
  • This halogen-pyrrole exchange is usually carried out at room temperature in a solvent such as e.g. Dimethyl sulfoxide or N, N-
  • the use of 4-fluoro-2-methyl-5-methylsulfonylbenzoic acid is particularly advantageous since the exchange takes place at room temperature.
  • the NaH serves as a salt generator and acid scavenger and is added in an amount of about two molar equivalents.
  • the Na salts of the reaction components pyrrole and hydrofluoric acid
  • the 2-methyl-5-methylsulfonyI-4-pyrrolyl-benzoic acid is obtained without further purification in good yield (approx. 78%) and in high purity.
  • the free acid is coupled with N- (benzyloxycarbonyl) guanidine (for the preparation of benzyloxycarbonyl (Z) guanidine, see M. Goodman et al., PCT Int. Appl. WO 9852917, 1998; K. Nowak , Rocz. Chem. 1969, 43, 231-232; R. Krug and K. Nowak, Rocz. Chem. 1967, 41, 1087-1091) on N- [N1- (benzyloxycarbonyl) amidino] -2-methyl- 5-methylsulfonyl-4- (1-pyrrolyl) benzamide.
  • N- (benzyloxycarbonyl) guanidine for the preparation of benzyloxycarbonyl (Z) guanidine, see M. Goodman et al., PCT Int. Appl. WO 9852917, 1998; K. Nowak , Rocz. Chem. 1969, 43, 231-232; R. Krug and
  • the Z-protecting group can be cleaved off by catalytic hydrogenation in accordance with the generally known conditions for this.
  • a catalyst e.g. a noble metal catalyst such as palladium, suitably on a support.
  • Particularly suitable solvents are e.g. Alcohols such as methanol or ethanol or amides such as DMF.
  • Hydrogenation is generally carried out at temperatures between about 0 ° and 100 ° C and pressures between about 1 and 200 bar.
  • acetone is used as the solvent in the catalytic hydrogenation and palladium (5-10% Pd-C) is used as the catalyst, and the reaction is carried out at temperatures of 20-30 ° C. and a pressure of 1-10 bar.
  • acids other than methanesulfonic acid can also be used for salt precipitation, in particular those mentioned in EP 0 699 666.
  • an effective process for the preparation of N- (diamino-methylene) -2-methyl-5- (methylsulfonyl) -4- (pyrrol-1-yl) benzamide, methanesulfonate (eniporide) is available, which is significantly improved previously known methods, both in terms of the number of synthetic steps and in terms of the overall yield.
  • N- (diaminomethylene) -2-methyl-5- (methylsulfonyl) -4- (pyrrol-1-yl) benzamide, methanesulfonate (eniporide) shows a good cardioprotective effect as Na + / H + - antiporter inhibitor and is suitable therefore especially for infarct treatment, infarct prophylaxis and for the treatment of angina pectoris.
  • the mixture is worked up by pouring onto 600 ml of ice water, double extraction with 400 ml of ethyl acetate, washing the organic phase with 1
  • the pyrrole salt is prepared from 20 mmol of pyrrole and 20 mmol of NaH in 5 ml of dimethyl sulfoxide and the mixture is stirred for about 1 hour.
  • the Na salt of the above F-acid (15.6 mmol acid, 15.6 mmol NaH, 80% in white oil, 20 ml DMSO) is also prepared.
  • the solutions are combined and stirring is continued for 3 hours at room temperature.
  • the reaction solution is then poured onto 150 ml of ice n and 150 ml of 1 N HCI are added. After suction and drying, the product is obtained in a yield of 78% and with an mp of 190-191 ° C.
  • the reaction is carried out as in 3.1. described by.
  • the acid component is 4-chloro-2-methyl-5-methylsulfonyl-benzoic acid. After heating at 65 ° C. for 6 hours, 68% of 2-methyl-5-methylsulfonyl-4-
  • the Z-protecting group is split off from 0.036 mol of N- [N1- (benzyloxycarbonyl) amidino] -2-methyl-5-methylsulfonyl-4- (1-pyrrolyl) benzamide in 400 ml of acetone, with 4 g of Pd- C-5% and hydrogen according to the usual conditions for catalytic hydrogenation.
  • the catalyst is then filtered off with suction, 4 ml of methanesulfonic acid are added, the mixture is stirred for about 1 hour with cooling and suction filtered. The residue is washed with acetone and ether and then dried. The end product is thus obtained in a yield of 97.9%, mp. 269-270 ° C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyrrole Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé de production du dérivé de benzoylguanidine N- (diaminométhylèn)-2- méthyl-5- (méthyl-sulfonyl)-4- (pyrrol-1-yl)- benzamide de la structure (I). Cette substance est un inhibiteur d'antiports Na+/H+ sélectif NHE-1.
PCT/EP2000/003455 1999-04-28 2000-04-17 Procede de production d'un derive de benzoylguanidine WO2000066552A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU41190/00A AU4119000A (en) 1999-04-28 2000-04-17 Method for producing a benzoylguanidine derivative

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19919349.5 1999-04-28
DE19919349A DE19919349A1 (de) 1999-04-28 1999-04-28 Verfahren zur Herstellung eines Benzoylguanidinderivates

Publications (1)

Publication Number Publication Date
WO2000066552A1 true WO2000066552A1 (fr) 2000-11-09

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PCT/EP2000/003455 WO2000066552A1 (fr) 1999-04-28 2000-04-17 Procede de production d'un derive de benzoylguanidine

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AU (1) AU4119000A (fr)
DE (1) DE19919349A1 (fr)
WO (1) WO2000066552A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2396295A1 (fr) 2009-02-12 2011-12-21 Merck Serono S.A. Dérivés d'acide phénoxyacétique

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0556672A1 (fr) * 1992-02-15 1993-08-25 Hoechst Aktiengesellschaft Benzoylguanidines amino-substitués possédant des propriétés antiarythmiques
EP0699666A1 (fr) * 1994-08-31 1996-03-06 MERCK PATENT GmbH Benzoylguanidines, heterocyclyques substitués
EP0704431A2 (fr) * 1994-08-28 1996-04-03 MERCK PATENT GmbH Dérivés d'acide benzoique ortho-substitués

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0556672A1 (fr) * 1992-02-15 1993-08-25 Hoechst Aktiengesellschaft Benzoylguanidines amino-substitués possédant des propriétés antiarythmiques
EP0704431A2 (fr) * 1994-08-28 1996-04-03 MERCK PATENT GmbH Dérivés d'acide benzoique ortho-substitués
EP0699666A1 (fr) * 1994-08-31 1996-03-06 MERCK PATENT GmbH Benzoylguanidines, heterocyclyques substitués

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BAUMGARTH M ET AL: "(2-METHYL-5-(METHYLSULFONYL)BENZOYL)GUANIDINE NA+/H+ ANTIPORTER INHIBITORS", JOURNAL OF MEDICINAL CHEMISTRY,US,AMERICAN CHEMICAL SOCIETY. WASHINGTON, vol. 40, no. 13, 1997, pages 2017 - 2034, XP000914594, ISSN: 0022-2623 *

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AU4119000A (en) 2000-11-17

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